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Abstract

Background

Pain is common in head and neck cancer (HNC) patients and may be attributed to the
malignancy and/or cancer treatment. Pain mechanisms and patient report of pain in
HNC are expected to include both nociceptive and neuropathic components. The purpose
of this study was to assess the trajectory of orofacial and other pain during and
following treatment, using patient reports of neuropathic pain and nociceptive pain
and pain impact.

Results

The majority of patients related their pain to the tumor and/or cancer treatment.
Whereas 59% reported their pain to be less severe than they expected, 29% were not
satisfied with their level of pain despite pain management during cancer therapy.
Worst pain was 3.0 ± 1.3 on a 0- to 5-point verbal descriptor scale. Pain intensity
was present at entry, highest at 2-week follow-up, declining towards the end of treatment
and persisting at 3-month follow-up. The most common neuropathic pain descriptors
chosen were aching (20%) and burning (27%); nociceptive words chosen were dull (22%),
sore (32%), tender (35%), and throbbing (23%), and affective/evaluative descriptors
were tiring (25%) and annoying (41%). 57% of patients reported continuous pain, and
combined continuous and intermittent pain was reported by 79% of patients.

Discussion

This study provides evidence that patients with HNC experience nociceptive and neuropathic
pain during RT despite ongoing pain management. The affective and evaluative descriptors
chosen for head and neck pain indicate considerable impact on quality of life even
with low to moderate levels of pain intensity. These findings suggest that clinicians
should consider contemporary management for both nociceptive and neuropathic pain
in head and neck cancer patients.

Background

Pain is common for the 35,310 people who are diagnosed with head and neck cancer (HNC)
in the United States annually [1,2]. HNC pain may arise due to tissue damage from multiple sources such as mucosal injury,
invasion of the tumor into somatic tissue (skin, muscle, bone) with inflammation or
ischemia, and nerve infiltration or compression [3]. Treatment for HNC involves single or multimodal therapy employing surgery, chemotherapy
(CT) and/or radiation (RT), all of which can damage somatic tissues and nerves. These
multiple sources of somatic tissue and neural damage from the tumor and cancer treatment
result in pain being experienced by all HNC patients [4].

Neuropathic pain is defined by The International Association for the Study of Pain
(IASP) as pain initiated or caused by a primary lesion or dysfunction in the nervous
system resulting in debilitating pain [5]. Damage to somatic and primary and/or central neurons commonly associated with nociceptive
pain may result in neuropathic pain [6-8]. This dysfunction in the nervous system may be exacerbated by persistent unrelieved
nociceptive pain associated with the tumor or cancer treatments (e.g., mucositis),
thereby producing neuropathic pain. Alteration in pain processing at peripheral sites
(such as with mucositis) and central levels (that may occur when mucositis pain is
persistent) produces characteristic sensory abnormalities such as hyperalgesia and
allodynia [9]. Hyperalgesia is defined as an increased response to a stimulus that is normally
painful and allodynia as pain due to a stimulus that does not normally provoke pain
[8].

One of the most feared consequences of cancer is the possibility of severe and uncontrolled
pain in patients with advanced cancer [10]. In patients with HNC, pain is reported in up to 85% of cases at diagnosis [11,12]. Pain due to soft tissue and bone destruction and nerve injury may involve inflammatory
and/or neuropathic mechanisms [13-19]. Further, it is estimated that 45% to 80% of all cancer patients have inadequate
pain management [20-22]. Barriers to adequate pain management include patients' reluctance to report pain
[23], current pain management practices by health care providers [24] and providers' negative ideas about and regulatory barriers to the use of opioids
[25]. In addition, limited understanding of the frequency and role of neuropathic pain
mechanisms and the lack of use of management approaches for neuropathic pain may compromise
symptom management in cancer patients.

Cancer pain causes increased morbidity, reduced performance status, increased anxiety
and depression, and diminished quality of life (QOL) [17,26-28]. Head and neck and oral pain management may be particularly challenging due to the
rich innervation of the orofacial region and because oral intake, swallowing, speech
and other motor functions of the head and neck and oropharynx are constant pain triggers.
In addition, the oral mucosa is susceptible to the effects of systemic chemotherapy
and regional radiotherapy, resulting in painful mucositis. The oral microbial flora
may cause secondary infection with attendant pain and morbidity.

Pain may be the first symptom in 20% to 50% of all cancer patients [10] due to the malignancy, and oral pain may arise from HNC in up to 85% [10,11] from metastatic disease in the head and neck or due to oral involvement in systemic
cancers (e.g., leukemia). In a recent study, investigators identified pain in 56%
of patients with HNC at diagnosis, and found mixed nociceptive and neuropathic pain
in 93% of those with pain [29]. In a retrospective study of 1,412 patients with oral cancer, pain was identified
as the first sign of cancer in 19%, and pain was commonly reported with tumor recurrence
[30]. Others reported cancer-related pain in 52% of hospitalized patients, with pain directly
due to tumor in 29% and to surgery in 50% [31,32]. In large surveys of pain characteristics in cancer including HNC [17,19], patients suffered pain associated with the tumor (87% to 92.5%), or cancer therapy
(17% to 20.8%) or both. In HNC, 78% of patients report pain in the head, face or mouth
and 54% in the cervical region or shoulder [19]. In HNC, pain is the major reason (up to 85%) for seeking care [33], but at diagnosis pain is usually of low intensity (mean 10-cm visual analogue scale
[VAS] = 3). Orofacial pain associated with cancer management is a well-recognized
adverse effect of treatment, but whether this represents nociceptive or neuropathic
mechanisms is not well defined. Pain due to oral mucositis is the most frequently
reported patient-related complaint impacting QOL during cancer therapy [34-42] and often results in severe pain for which opioid analgesics are prescribed [38,43-45], sometimes with additional impaired QOL. Successful pain management requires knowledge
of, and attention to, multiple pain mechanisms that may culminate in the patient's
pain.

In HNC patients, neuropathic pain has not been well characterized in terms of sensory
report (location, intensity, quality and pattern) or sensory quantification (allodynia
and hyperalgesia). Grond et al. [46] reported that 30% of HNC patients suffered from neuropathic pain as result of the
cancer or its treatments. In addition to neuroplasticity as a mechanism for neuropathic
pain, other mechanisms may play a role in producing neuropathic pain associated with
mucositis that may be conditioned by inflammatory mediators (e.g., tumor necrosis
factor-alpha [TNF-α]), which play a central role in the activation of cytokines and
are elevated in mucositis [47]. TNF-α is known to be involved in mediation of neuropathic pain and hyperalgesia
[48]. Other chemical mediators implicated in neuropathic pain include reactive oxygen/nitrogen
species, bradykinin, substance P and other cytokines that are upregulated in mucositis
[47]. Investigators also have demonstrated changes in dorsal horn processing of nociceptive
stimuli that result in neuropathic pain [49]. These mechanisms may result in neuropathic pain associated with tissue damage that
occurs from HNC or its treatment. Previous investigators have not characterized the
pain in HNC patients using multidimensional pain measures. The purpose of this paper
is to describe the experience and trajectory of sensory pain (location, intensity,
quality, and pattern) in patients with HNC undergoing cancer treatment using PRO,
including neuropathic and nociceptive pain descriptors.

Methods

We conducted a 3-month repeated-measures study to describe the trajectory of pain
and pain descriptors in consecutive patients with HNC. The study was approved by the
Institutional Review Board at the University of Washington for initial data collection
and at the University of Illinois at Chicago for ongoing data analysis.

Sample

Eligible subjects: (a) had a diagnosis of HNC; (b) spoke and read English; and (c)
had pain related to the cancer or to cancer therapy during the week prior to enrolling.
Patients were excluded if they: (a) had surgery within one month; (b) were physically
unable to complete study procedures; or (c) were mentally unable to complete study
questionnaires because of brain metastases or developmental problems, as measured
by a Mini-Mental State Exam (MMSE) [50] (defined as a score of 20 or less). The MMSE is an 11-question scale designed to
efficiently screen a person's cognitive functioning. Scores 19 and below represent
cognitive impairment [50].

Of the 151 patients eligible for the study, 27 refused and 124 consecutive patients
participated (Table 1). The participants included 95 men and 29 women. Their mean age was 54.7 ± 12.3 years.
Most of the participants were Caucasian (88%), with 3% Hispanic and 2% African American.
Other demographics of the patients are shown in Table 1. The primary tumor site was oral cavity/oropharynx (46%), major salivary gland (23%),
maxillary sinus (12%), larynx (11%), and unknown (8%). The tumor stage at enrollment
was Stage I in 17%, Stage II in 14%, Stage III in 14% and Stage IV in 46%; 10% were
unknown primary. The histologic diagnoses were: adenocarcinoma (13%); adenoid cystic
carcinoma (31%); mucoepidermoid carcinoma (13%); squamous cell carcinoma (37%); and
miscellaneous (7%). Most (68.5%) patients had surgery prior to radiation therapy.

Procedures

Medical and dental providers in the cancer clinic introduced patients to the investigators
in person. A research team member informed patients about the study and scheduled
data collection to coincide with a scheduled clinic appointment if patients were eligible
and agreed to participate. The researcher obtained a signed informed consent, administered
the MMSE to confirm eligibility, and interviewed the patient to complete a demographic
data form. Patients were seen by their oncology providers for routine clinic follow-up
visits. After the clinic visit, patients completed the valid and reliable 1970 version
of the McGill Pain Questionnaire [51] at 2 weeks, 4 weeks and 3 months after the baseline measures to record pain in the
extra-oral and intra-oral environments. Pain location was measured as the number of
pain sites marked on a body outline. Pain intensity was measured as current, least,
and worst pain using the 0–5 verbal descriptor scale. Pain quality was measured as
descriptors selected from a list of 78 that represented sensory (PRI-S), affective
(PRI-A), evaluative (PRI-E), miscellaneous (PRI-M), and total (PRI-T) pain, as well
as number of words chosen (NWC) [52-54]. Pain pattern was measured as descriptors selected from a list of nine words representing
continuous, intermittent, and brief patterns of pain. The following information was
recorded from interview or medical record review: (1) gender; (2) age; (3) diagnosis(es);
(4) medication(s) taken, including systemic and topical anesthetics and analgesics
and time of last dose; and (5) RT dose and CT agent(s).

Research staff members entered data in CRUNCH4 (Crunch Software Corporation, San Francisco,
CA) and exported it to SPSS (SPSS, Inc., Chicago, IL) for data analysis. We present
descriptive statistics for the pain location, intensity, quality, and pattern, as
well as the number of nociceptive and neuropathic descriptors reported at each measurement
time point. Pain quality findings are reported for the first pain site reported that
was located in the head and neck region. We plotted scores and calculated repeated-measures
ANOVAs over time for pain scores reported during the 3-month study.

Prior to study entry, the majority of patients reported pain for 0–6 months (77%),
7–12 months (5.6%), 13–23 months (4%), or more than 2 years (12.9%). At baseline,
patients associated their pain with their cancer (21%), surgery (53.2%), or both tumor
and surgery (20.5%). On average, patients reported 2.1 ± 2.2 pain sites. Pain measures
at baseline are shown in Table 2. The distributions of the pain locations are presented for the first site marked
and for all sites marked (Table 3). The neuropathic, nociceptive, affective, and evaluative pain descriptors are shown
in Table 4.

Current pain at visit one was 1.51 ± 1.01, worst pain was 3.03 ± 1.26; those increased
at time 2, where current pain was 1.60 ± 0.81 and worst was 3.18 ± 1.15, and decreased
at subsequent time points. The scores for current and worst pain, pain pattern, and
number of pain sites were not significantly different by the type of cancer therapies
that the patient received. The subjects with both chemotherapy and radiation treatments
reported statistically significant higher PRI-T scores (mean, 19.58 vs. 12.56, t =
-2.29, p < .024 than the subjects with other therapies (e.g., radiation only, surgery and radiation;
or chemotherapy, radiation and surgery). At time 3, worst pain was 2.89 ± 1.23, and
at time 4 worst pain was 2.54 ± 1.40, current pain 1.02 ± 1.07 and least pain 0.60
± 0.81 (Figure 4). A highly correlated linear trend was seen between the number of nociceptive and
neuropathic words chosen during treatment. Patient demographics, including age, gender,
ethnicity and income, did not correlate with the variables assessed.

We estimated adequacy of analgesic prescription by calculating a pain management index
(PMI) as suggested by Cleeland [55,56]. We subtracted the worst pain level score from the analgesics step score to produce
a PMI score. A negative PMI score indicated inadequate analgesic prescription (under-treatment
of pain) and 0 or positive PMI scores indicated satisfactory analgesics. Based on
Cleeland's PMI, 63.7% of the patients were taking prescriptions satisfactory for their
pain intensity level; 23.4% were taking prescriptions that represented undertreatment
for the level of their pain intensity. PMI scores could not be calculated for those
for whom drug data were missing.

Discussion

HNC patients were enrolled in the study during cancer treatment when pain was reported.
Patients attributed their pain to the cancer, prior surgical treatment or the ongoing
radiation therapy for HNC. Pain was discomforting on average at entry (worst pain
intensity 3.0 ± 1.3), and it was less than anticipated in more than half of the patients,
as expected in about one-fifth and worse than expected by some. In our survey, pain
was reported first in the head and neck or oral cavity by 79% (n = 98) of the participants.

In a previous study, pain was reported by patients with oral squamous cell carcinoma
at presentation in 39% of 138 cases and correlated with tumor stage [57]. Pain at diagnosis of HNC has been variable, with pain reported in up to 85% of patients
[58]. Investigators of one study found that 65.5% of 1,070 cancer patients reported pain
prior to cancer therapy, whereas pain was less common at diagnosis in another study
(48.1%) [59,60]. In a recent study, pain was identified in 56% of patients with HNC at diagnosis
[29]. Pain at diagnosis is typically of low intensity discomfort as the first symptom
leading to diagnosis [58]. The most common qualitative descriptions of pain were aching, dull, or pressing
[33]. Interestingly, patients who present with pain before treatment develop significantly
higher impairment scores due to pain during and following treatment [59], suggesting that sensitization occurs. We found similar findings in our trial, where
report of nociceptive and neuropathic pain at entry predicted pain experience during
and following therapy.

Neuropathies are commonly reported in patients with malignancy (1.7%–5.5%) and may
be due to direct effects of the tumor, paraneoplastic syndromes and/or treatment-related
toxicity [61-64]. Neurotoxicity is increased in patients with pre-existing nerve damage [65] and with nutritional deficiencies [66]. However, the incidence of paraneoplastic neuropathies occurring in the orofacial
region is unclear. In our survey, neuropathic descriptors of pain were selected by
a total of 73% of subjects (n = 91), suggesting that neuropathic pain is common in
patients with HNC. In a previous study, mixed nociceptive and neuropathic descriptors
were chosen by 93% of HNC patients reporting pain at diagnosis [29]. The affective and evaluative impact of pain in head and neck and oral sites in these
patients indicates the significant impact of head and neck pain, in which neuropathic
mechanisms are common. The finding of a linear trend in the number of nociceptive
and neuropathic words chosen during treatment suggests that the pain experience may
be due to both nociceptive and neuropathic pain. Patient demographics, including age,
gender, ethnicity and income, did not correlate with the variables assessed. Approximately
one-third of patients reported continuous pain, 40% reported continuous plus intermittent
pain and 15% reported intermittent pain associated with oral function such as with
eating or swallowing. We did not identify a shift from neuropathic and nociceptive
word choice during treatment, suggesting that both mechanisms are associated with
pain at entry and during RT.

The most common acute oral side effect of chemotherapy and radiotherapy is oral mucositis
[67]. Oral mucositis and associated pain is reported to be the most distressing symptom
in radiotherapy, with increasing pain intensity and pain interference scores by week
3, peaking at week 5 [68] and persisting for weeks following irradiation [35]. Mucositis pain is common (58%–75%) and interferes with daily activities in approximately
one-third of subjects [69-74] and with social activities and mood in 50%–60% [35]. Combined chemotherapy and radiation therapy results in increased frequency, severity
and duration of mucositis [73-76]. These findings were reflected in the pain report of subjects in this study, where
pain intensity remained essentially unchanged during RT despite use of analgesics
and other pain management. In addition to mucositis, some cytotoxic agents may cause
jaw pain and neuropathy (e.g., vincristine, vinblastine, platinum).

Surgical procedures commonly result in acute nociceptive orofacial pain and establish
conditions that may lead to painful post-surgical neuropathy. In addition to tissue
injury at tumor resection, morbidity is increased by concomitant procedures such as
radical neck dissection [77]. In this study, patients reported that pain was related to the tumor (21%), and related
to cancer treatment (53.2%) or both (20.5%), indicating that patients felt that the
majority of pain was treatment-related. Resection of the mandible inevitably leads
to sensory impairment [78], with 50% of recipients experiencing regional hyperalgesia or allodynia. At 2–5 years
post maxillectomy, 88%–90% of patients reported persistent pain [79]. In an analysis of patients treated for laryngeal cancer, ablative surgery with adjuvant
chemo- and/or radiotherapy was associated with increased chronic pain and psychosocial
morbidity compared to that of patients treated by chemoradiation alone [80], underscoring the impact of surgical intervention. Investigators of another study,
examining pain scores following HNC surgery, showed that the highest scores were for
the oral cavity, followed by the larynx, oropharynx and nasopharynx [79]. In a large survey of surgically treated oral cancer patients, functional problems
were reported postoperatively in more than 50% of cases [60]. At review (= 6 months post-surgery), impairment due to moderate to severe pain was
found in 34.3% of cases [60]. In two studies, the most frequent pain locations were the shoulder (31%–38.5%),
neck (4.9%–34.9%), TMJ (4.9%–20.1%), oral cavity (4.2%–18.7%) and the face and other
head regions (4.2%–15.6%) [60,81], reflecting morbidity secondary to surgical management [77,82]. Fortunately, there is a tendency for post-treatment symptoms to improve with time
[83]. By 60 months post surgery, a smaller proportion of patients (14.9%) (n = 74) had
persisting pain [81]. In cancer patients, the postoperative pain experience typically is characterized
by acute pain persisting 1–2 months, with a gradual improvement over time [83-85]. However, long-term HNC survivors (> 3 years) still suffer significantly more pain
and functional problems than matched control subjects, even though there is a relative
return towards normal function [81,83,85]. Persisting pain following surgery may involve inflammatory and neuropathic pain
mechanisms, depending on the extent of surgery and its anatomic location. Functional
consequences are often secondary to pain and may involve wound contractures and scarring
[81]. Our study provides evidence that patients with HNC experience nociceptive and neuropathic
pain. These findings are supported in prior studies, where 30% of HNC patients suffered
from neuropathic pain in one study [46], and the majority of patients reported pain in another study [29].

The affective and evaluative descriptors chosen for head and neck pain indicate considerable
impact on quality of life, even with low to moderate levels of pain intensity. Effective
management requires accurate diagnosis of the multifaceted etiology of orofacial pain
in cancer patients [47,86]. Pain intensity scores did not progress during treatment with ongoing pain management
and were lower than at entry at the final assessment visit following RT. The findings
suggest that expert medical management during cancer therapy can modulate the pain
experience, despite the impact of radiation and chemotherapy. The PMI indicated that
63.7% of the patients were taking prescriptions satisfactory for their pain intensity
level, while 23.4% were not adequately treated for their pain level; 10.5% of patients
were on step 1 analgesics (non-opioid analgesics), 8.1% step 2 opioid (mild opioids),
20.2% step 3 opioids and 21% prescribed adjuvant analgesics. The other patients were
using combinations of analgesics and adjuvant drugs.

Nociceptive pain is managed with treatment of the cause and topical anesthetics and
analgesics, with reliance upon systemic analgesics. Neuropathic pain is typically
more difficult to manage and in contrast relies upon locally acting anesthetics and
centrally acting antidepressant and anti-convulsant medications, along with biopsychosocial
treatment and systemic analgesics. Future research regarding pain in head and neck
cancer patients should consider neuropathic and nociceptive pain-related complaints
along with quantitative sensory testing to confirm neuropathic pain. In clinical practice,
clinicians should consider contemporary management for both nociceptive and neuropathic
pain in head and neck cancer patients.

Conclusion

Pain experienced during radiation therapy for head and neck cancer is common. Neuropathic
pain descriptors were chosen by 73% of patients and a linear trend was seen in number
of neuropathic and nocicpetive descriptors chosen by pateints during therapy. Pain
was common despite ongoing pain management during therapy. This study shows that pain
during radiation therapy have both nocicpetive and neeuropathic qualities.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

JE reviewed study data and drafted the manuscript. YOK performed the statistical analysis.
DJW conceived of the study, and participated in its design and coordination and helped
to draft the manuscript. All authors contributed to and approved the final manuscript.

Acknowledgements

This research was made possible by Grant Number RPG-96-001-03-PBP from the National
American Cancer Society, awarded to Diana J. Wilkie. Its contents are solely the responsibility
of the authors and do not necessarily represent the official views of the American
Cancer Society. The authors thank Kevin Grandfield for editorial assistance.